PETACON's purpose is to develop a way to manage the risk of serious, but uncommon, side effects due to differing responses to nonsteroidal antinflammatory drugs, or NSAIDs. These drugs are used to relieve pain and inflammation and are among the most common medications consumed worldwide. According to the American Gastroenterological Association, more than 30 million people take over-the-counter and prescription NSAIDs every day for pain, headaches, and arthritis.

More than 30 types of NSAIDs are currently on the market, and people differ in their preferences, often claiming that some, but not others, work for them. Like all drugs, NSAIDs come with their downsides and have long been recognized to cause stomach upsets, sometimes life- threatening bleeds from the gastrointestinal (GI) tract.

"There's a great need to understand how people differ in their response to NSAIDs and how their use might be tailored to the needs and susceptibilities of the individual patient," says FitzGerald.

"This comprehensive project will use the latest technologies to aid patients and their health care providers in selecting the best alternative from the available treatments," said Susan Shurin, M.D., acting director of the NHLBI. "NSAIDs are among the most commonly used drugs, and their benefits and toxicities have been variable and difficult to predict. The potential ability to personalize use of this important class of agents is scientifically important and has considerable public health value."

More than a decade ago, NSAIDs less likely to cause GI problems were launched on the market. These drugs, which included Vioxx and Celebrex, targeted COX-2, one of two COX enzymes blocked by older NSAIDs, such as Aleve and Naprosyn. These newer drugs turned out to cause heart attacks, heart failure, and strokes in a small proportion of the patients who consumed them.

Remarkably, researchers still understand poorly how to predict whether patients will gain relief from NSAIDs — presently it's a matter of trial and error. Similarly, they have no scientific basis for predicting patients more likely to have serious risks or to detect the gradual emergence of such risks.

PENTACON aims to use the power of contemporary "omics" technologies -- genomics, proteomics, metabolomics -- to address individual response to NSAIDs. Using NSAIDs that differ in their preferences for blocking the two COX enzymes, the researchers will seek molecular signatures that discriminate drug action in cells and model systems. PENTACON collaborators will then integrate this information with clinical trial data to understand how NSAIDs perturb biological networks, looking for both benefit and risk.

"It is our hope that these studies will allow us to predict likely pain-relieving benefit and cardiovascular risk with a level of precision that transcends the art of medicine," says FitzGerald. "Hopefully this work will reduce to the level of an app, where a practitioner can enter information – a person's clinical details, with genomic and epigenomic data, for example, and after a test dose, drug levels and metabolic response — to receive an answer to whether you should be on an NSAID, and if so, which one, at what dose and whether you should keep taking it."

To be sure, it is an ambitious program that will unfold over the next decade: "This may seem like a long time, but it has been almost a decade since Vioxx was withdrawn and if we had commenced a program like this back then, the answer would be in. Perhaps the value of that drug might have been conserved for those who can use it safely," said FitzGerald. "If we succeed, we may set a paradigm for the progressively more personalized use of other common drug classes, such as those used to treat clinical conditions as variable in their origin as pain."

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